Research on mechanisms for vascular action of adrenomedullin

肾上腺髓质素是一种血管舒张肽，循环肾上腺髓质素的主要来源是血管壁。肾上腺髓质素的血管作用最初被认为仅仅是由于cAMP的产生增加。例如，非内皮依赖性血管舒张。然而，我们发现内皮剥脱实质上减少了肾上腺髓质素在啮齿动物主动脉环中的血管舒张作用。此外，这种肾上腺髓质素诱导的内皮依赖性血管舒张主要是通过激活磷脂酰肌醇3-激酶（PI 3-K）/Akt通路来实现的。这一信号通路参与多种重要的生物学作用，如抗凋亡、组织保护以及激活内皮型一氧化氮合酶（eNOS）等。肾上腺髓质素消除缺血/再灌注肾损伤。使用肾上腺髓质素基因敲除小鼠的研究表明，肾上腺髓质素在胚胎血管形成中起重要作用。肾上腺髓质素转基因小鼠对缺血/再灌注肾损伤具有抵抗性，肾上腺髓质素敲除小鼠则相反。这些结果表明，内源性肾上腺髓质素可能发挥重要作用，作为一种组织生存因子。

Adrenomedullin is a vasodilatory peptide and major source of circulating adrenomedullin is the vascular wall. The vascular action of adrenomedullin was at first considered to solely due elevated cAMP production, I. e., endothelium-independent vasodilation. However, we found that endothelial denudation substantially reduced the vasodilatory action of adrenomedullin in rodent aortic rings. Furthermore, this adrenomedullin-induced endothelium-dependent vasorelaxation is exerted mostly through activation of the phosphatydil inositol 3-kinase (PI3-K)/Akt pathway. It has been well established that this pathway is involved in various important actions such as anti-apoptosis and tissue protection as well as activation of endothelial nitric oxide synthase (eNOS).Furthermore, we have reported that expression of the adrenomedullin gene is upregulated by hypoxia. Adrenomedullin abrogates ischemia/reperfusion renal injury. Studies using adrenomedullin gene knockout mice revealed that adrenomedullin plays an important role in vascular formation in embryos. Adrenomedullin transgenic mice were resistant to ischemia/reperfusion renal injury and adrenomedullin knockout mice vice versa. These findings suggest that endogenous adrenomedullin may play an important role as a tissue survival factor.